The simple assumption that amyloid is the driving factor underlying the clinical symptoms of dementia and the formation (s) of NFTs in AD (Hardy and Allsop, 1991) which has since been modified. Interestingly, Dr. Alzheimer wrote “…the plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system” (Alzheimer, 1911). More recently, Mesulam (1999) stated, “It seems as if the A plaques appear at the wrong time and in the wrong places with respect to the clinical dementia and there is little evidence that they cause the NFT”. In light of the continued lack of efficacy of human anti amyloid strategies in AD, these comments may prove to be prescient. By contrast, NFT pathology displays a highly significant LY317615 web correlation with cognitive impairment in AD (Giannakopoulos et. al., 2003) and occurs within the hippocampus very early in the disease processes (Braak and Braak, 1991). However, clinical pathologic data indicate that the hippocampus remains highly malleable despite the abundance of NFT pathology during the onset of AD (Gary et al., 2014).Hippocampal Procyanidin B1 site structural plasticity in MCI and ADIn AD, ultrastructural counts of synapse numbers indicate a reduction in the inner and outer layers of the dentate gyrus (Scheff et al., 1996, 1998), which receives extensive input from the entorhinal cortex (Simonian et al., 1994). Another investigation found a reduction in synapses within the supragranular band below the inner molecular layer in AD (BertoniFredarri et al., 1990). Although decreases in synaptic density are more highly correlated with the degree of cognitive impairment than classic pathological changes related to AD (Terry et al., 1991; Scheff et al., 2006; DeKosky and Scheff, 1990; Scheff and Price, 2003; Sze et al., 1997), very few studies have investigated synaptic contact integrity or evidence for a neuroplastic response in the hippocampus in individuals with MCI or early AD. A series of studies, which combined unbiased stereology with electron microscopy, failed to demonstrate a significant difference in the total number of synapses within the outerNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagemolecular layer of the hippocampus between individuals with aMCI compared to NCI, but there was a significant decrease between early AD and MCI as well as NCI (Scheff et al., 2006). The reduction in synapses in early AD compared to both NCI and MCI did not appear to be associated with a loss of granule cells (West et al., 2004) but likely reflected a loss of afferent innervation from the ipsilateral entorhinal cortex (Hyman et al., 1987; Gomez-Izla et al., 1996; Yasuda et al., 1995; Scharfman and Chao, 2013). Notably, this loss of entorhinal input to the hippocampus has been shown to initiate an extensive sprouting of cholinergic innervation into the molecular layer of the hippocampus (Geddes et al., 1985), where neuritic plaques preferably accumulate, thus leading to a hypothesis that reactive cholinergic sprouting contributes to the pathogenesis of A plaque formation (Geddes et al., 1986). This compensatory structural remodeling within the hippocampus illustrates the neuroplastic capacity of this region to counteract (or contributes to) mounting pathology. By contrast, a subsequent study using the same cohort of cases (Scheff et al., 2006) reported a significant reduction in total synapse number in the striatum radiatum region of the hippoc.The simple assumption that amyloid is the driving factor underlying the clinical symptoms of dementia and the formation (s) of NFTs in AD (Hardy and Allsop, 1991) which has since been modified. Interestingly, Dr. Alzheimer wrote “…the plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system” (Alzheimer, 1911). More recently, Mesulam (1999) stated, “It seems as if the A plaques appear at the wrong time and in the wrong places with respect to the clinical dementia and there is little evidence that they cause the NFT”. In light of the continued lack of efficacy of human anti amyloid strategies in AD, these comments may prove to be prescient. By contrast, NFT pathology displays a highly significant correlation with cognitive impairment in AD (Giannakopoulos et. al., 2003) and occurs within the hippocampus very early in the disease processes (Braak and Braak, 1991). However, clinical pathologic data indicate that the hippocampus remains highly malleable despite the abundance of NFT pathology during the onset of AD (Gary et al., 2014).Hippocampal structural plasticity in MCI and ADIn AD, ultrastructural counts of synapse numbers indicate a reduction in the inner and outer layers of the dentate gyrus (Scheff et al., 1996, 1998), which receives extensive input from the entorhinal cortex (Simonian et al., 1994). Another investigation found a reduction in synapses within the supragranular band below the inner molecular layer in AD (BertoniFredarri et al., 1990). Although decreases in synaptic density are more highly correlated with the degree of cognitive impairment than classic pathological changes related to AD (Terry et al., 1991; Scheff et al., 2006; DeKosky and Scheff, 1990; Scheff and Price, 2003; Sze et al., 1997), very few studies have investigated synaptic contact integrity or evidence for a neuroplastic response in the hippocampus in individuals with MCI or early AD. A series of studies, which combined unbiased stereology with electron microscopy, failed to demonstrate a significant difference in the total number of synapses within the outerNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagemolecular layer of the hippocampus between individuals with aMCI compared to NCI, but there was a significant decrease between early AD and MCI as well as NCI (Scheff et al., 2006). The reduction in synapses in early AD compared to both NCI and MCI did not appear to be associated with a loss of granule cells (West et al., 2004) but likely reflected a loss of afferent innervation from the ipsilateral entorhinal cortex (Hyman et al., 1987; Gomez-Izla et al., 1996; Yasuda et al., 1995; Scharfman and Chao, 2013). Notably, this loss of entorhinal input to the hippocampus has been shown to initiate an extensive sprouting of cholinergic innervation into the molecular layer of the hippocampus (Geddes et al., 1985), where neuritic plaques preferably accumulate, thus leading to a hypothesis that reactive cholinergic sprouting contributes to the pathogenesis of A plaque formation (Geddes et al., 1986). This compensatory structural remodeling within the hippocampus illustrates the neuroplastic capacity of this region to counteract (or contributes to) mounting pathology. By contrast, a subsequent study using the same cohort of cases (Scheff et al., 2006) reported a significant reduction in total synapse number in the striatum radiatum region of the hippoc.
